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J. Biol. Chem., Vol. 281, Issue 50, 38376-38384, December 15, 2006
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Apoptotic Cells, through Transforming Growth Factor-
, Coordinately Induce Anti-inflammatory and Suppress Pro-inflammatory Eicosanoid and NO Synthesis in Murine Macrophages*
1213
From the
Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro RJ 21944-970, Brazil and Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206
Apoptotic cells are rapidly engulfed by adjacent tissue cells or macrophages before they can release pro-inflammatory/proimmunogenic intracellular contents. In addition, recognition of the apoptotic cells is actively anti-inflammatory and anti-immunogenic with generation of anti-inflammatory mediators such as transforming growth factor-
(TGF-) and anti-inflammatory eicosanoids. Here, we have investigated the role played by the induction of TGF- in the coordinate expression of anti-inflammatory eicosanoids or peroxisome proliferator-activated receptor-
and in the suppression of pro-inflammatory lipid mediators and nitric oxide (NO). By use of a dominant negative TGFII receptor, TGF- signaling was blocked, and its participation in the consequences of apoptotic cell stimulation was determined. The induction of TGF- itself could be attributed to exposed phosphatidylserine on the apoptotic cells, which therefore appears to drive the balanced inflammatory mediator responses. Arachidonic acid release, COX-2, and prostaglandin synthase expression were shown to be significantly dependent on the TGF- production. On the other hand, a requirement for TGF- was also shown in the inhibition of thromboxane synthase and thromboxanes, of 5-lipoxygenase and sulfidopeptide leukotrienes, as well as of inducible nitric-oxide synthase and NO. TGF--dependent induction of arginase was also found and would further limit the NO generation. Finally, apoptotic cells stimulated production of 15-lipoxygenase and 15-hydroxyeicosatetraenoic acid, a potentially anti-inflammatory pathway acting through peroxisome proliferator-activated receptor-, and lipoxin A4 production, which were also up-regulated by a TGF--dependent pathway in this system. These results strongly suggest that the apoptotic cell inhibition of pro-inflammatory mediator production is pleiotropic and significantly dependent on the stimulation of TGF- production.
Received for publication, May 30, 2006 , and in revised form, October 11, 2006.
* This work was supported in part by National Institutes of Health Grants HL81151 and HL67671. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Both authors contributed equally to this work.
2 Recipient of Long Term Fellowship LT-00606-2002 from the Human Frontier Science Program.
3 To whom correspondence should be addressed: Program in Cell Biology, Dept. of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. E-mail: hensonp{at}njc.org.
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